Despite the recent progress that has been made in the diagnosis and treatment of various cancers, the long-term survival rate for cancer patients has not changed significantly in the last decade as the clinical outcome of a particular cancer is usually based on timely diagnosis. For example, Stage I ovarian cancer can typically be cured in 90% of all cases, while the five-year survival rate for patients with advanced forms of this disease (e.g., Stage III or IV) is less than 21%. As such, the prospects for significant improvements in cancer survival reside in early diagnosis.
Current diagnostic assays for many cancers are antigen-based and rely on the detection of circulating proteins that are associated with the particular cancer. These assays rely on the expression, synthesis, and release of specific proteins by cells (e.g., tumor cells) either by active secretion or shedding, or as a consequence of cell death (either necrosis or apoptosis). As such, these antigenic proteins must “escape” the primary site of disease, saturate the antigen-processing capacity of the individual's immune components, gain access to the circulation, and reach a sufficient steady-state concentration to be detected by enzyme- or radio label-based immunoassays. These events usually occur well after the initial establishment of disease (e.g., a neoplastic transformation event and tumor foci development). Thus, and despite the fact that certain specific antigenic epitopes exhibit common recognition among patients with the same tumor types, the use of these antigen-based cancer assays have not been widely accepted into clinical practice and many individual countries differ in the use of these potential diagnostic factors.
One such antigen, which has not been widely accepted as a reliable marker for cancer detection and diagnosis, is cathepsin D (CD). Increased levels of CD were first reported in several human neoplastic tissues more than 20 years ago (Reid, et al. 1986). Several years later, the first clinical studies found CD related to metastasis-free survival and disease-free survival in breast cancer patients (Thorpe, et al. 1989). Since then, numerous clinical studies have suggested a connection between CD levels and prognosis, incidence of metastasis, tumor aggressiveness and the degree of chemoresistance in a variety of solid tumors (Leto, et al. 2004; Ferrandina, et al. 1997). Other studies, however, have found conflicting results regarding the use of CD as a marker for cancer by employing different methodologies for CD quantification, different criteria for patient and diagnosis selection, and different durations of follow-up periods (Leto, et al. 2004). Additionally, previous studies that have examined the diagnostic and prognostic value of CD in cancer have been further complicated by the fact that there are several forms of CD in a tissue at the same time including procathepsin D (pCD), intermediate enzymatically active CD, mature heavy and light chain CD, as well as different forms of post-translationally modified pCD.
The roles of these additional forms of CD in cancer development have also been investigated. For example, the mitogenic effect of secreted pCD on breast cancer cells was first proposed over 20 years ago (Vignon, et al. 1986). Since that time, studies have demonstrated that pCD secreted from cancer cells serves as an autocrine growth factor for breast (Fusek and Vetvicka, 1994), prostate (Vetvicka, et al. 1998), ovarian (Bazzett et al. 1999) and lung cancer cells (Vetvicka, et al. 2004). Further, breast cancer cells with down-regulated expression of pCD by either antisense gene transfer (Glondu, et al. 2002), RNA interference (Ohri, et al. 2007) or ribozymes (Vashishta, et al. 2007) have displayed reduced growth in vitro and in vivo. Tumor growth has also been shown to be inhibited by anti-pCD antibodies in vivo and in vitro (Vetvicka, et al. 1997), and it has also been found that binding to cancer cells as well as pCD mitogenic potential is blocked by antibodies specific for the propeptide part of pCD (Vetvicka, et al. 1999).
Despite the extensive research into CD and pCD, and their respective roles in cancer, the use of CD or pCD, as a reliable marker for the detection and diagnosis of cancer still remains controversial. Indeed, some recent studies have suggested that CD may be used as a marker in lung cancer (Lou, et al. 2007) and colorectal cancer (Kaneko, et al. 2007), whereas other studies examining the role of CD in breast cancer have found exactly the opposite results (Kristek, et al. 2007; Fernandez-Aguilar and Noel, 2008) or only a questionable correlation between CD and cancer (Barthelli, et al. 2007). These insufficient and inconsistent findings recently led the American Society of Clinical Oncology not to recommend the use of CD as a tumor marker in breast cancer (Harris, et al. 2007).